Z and Mmalton-1-antitrypsin deficiency-associated hepatocellular carcinoma: A genetic study

Paola Francalanci, Filippo M. Santorelli, Simona Saccani, Maria F. Bonetti, Daniela Medicina, Pierpaolo Coni, Gavino Faa, Francesco Callea

Research output: Contribution to journalArticlepeer-review


Background: The histological hallmark of α-1-antitrypsin deficiency (AATD) is the presence of periodic acid-Schiff diastase (PASD)-resistant positive globules in hepatocytes, with a heterogeneous distribution. It is noteworthy that hepatocellular carcinoma (HCC) arises specifically from the AAT-negative areas but the reason for this remains unclear. Aim: To determine whether the different distribution of AAT globules within neoplastic and non-neoplastic hepatocytes is the result of a self-induced correction of the genetic defect. Patients and Methods: Two HCV-positive patients with AATD-associated HCC were studied. One patient harboured a compound heterozygous PiSZ genotype whereas the other showed the rarer PiMMmalton in heterozygosity. In both cases, neoplastic hepatocytes appeared globule devoid, while non-neoplastic hepatocytes showed intracytoplasmic accumulation of PASDpositive globules. Laser-assisted microdissection was used to assess a genotype/phenotype correlation in single liver cells from HCC and from non-neoplastic hepatocytes. Results: Direct sequencing of DNA purified from globule-devoid and globule-filled hepatocytes demonstrated that all liver cells carried the same mutant genetic background. Conclusion: Our findings indicate that (i) both variants of HCC arising in AAT deficiency (Z and Mmalton) do not accumulate the mutant protein and (ii) the different phenotypic appearance of hepatocytes is not the result of a retromutation during neoplastic transformation, but other mechanisms should be investigated.

Original languageEnglish
Pages (from-to)1593-1596
Number of pages4
JournalLiver International
Issue number10
Publication statusPublished - 2009


  • AAT globule
  • Genetic analysis
  • HCC

ASJC Scopus subject areas

  • Hepatology


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